Project 5 represents a continuation of a highly productive program initiated as part of the original Program project in Vascular Biology and Medicine. A key focus of the work pursued under this grant related to the effects of lipid lowering on vascular function. Notably, the Vascular Medicine and Biology Program Project supported seminal work demonstrating an improvement in coronary vasodilatation in response to the endothelial-dependent vasodilator acetylcholine when patients underwent lipid lowering and/or antioxidant treatment, published in The new England Journal of Medicine. The current project will embark in new directions. First, the role of endothelin in unstable and stable coronary lesions will be proved. These studies will test the hypothesis that endothelin-mediated vasoconstriction plays a role in flow impairment in the acute coronary syndromes. These studies will involve selective inhibitors of endothelial A or B type receptors. Studies from Dr. Libby's laboratory and others have documented altered endothelin gene expression in atheroma. This aspect will be pursued, in conjunction with the Vascular pathology Core, in atherectomy specimens. Further studies will test the hypothesis that coronary risk factors (e.g. hypercholesterolemia) change basal vascular tone in an endothelin-dependent manner. Another aim of this project will test the role of endothelin in pulmonary hypertension, primary, secondary, and hypoxia-induced. This project will involve observations on adult patient, and in conjunction with the Boston Adult Congenital Heart Disease Service shared between the Cardiovascular Division of the Brigham and Women's Hospital and Children's Hospital medical Center, younger-age patients will be included in the studies as appropriate. Once more, the Vascular pathology Core laboratory will aid in the analysis of biopsy specimens obtained from patients with pulmonary hypertension. In a third specific aim, the role of endothelin in vasomotor alterations associated with various cardiac risk factors will be explored, using the selective endothelin antagonist and the peripheral circulation probed by forearm studies. These latter studies will utilize the expertise of Dr. Creager, the project leader of Project 4.